The leukaemia forms chronic myeloid leukaemia (or chronic myelogenous leukaemia; CML), acute lymphatic leukaemia (ALL) and acute myeloic leukaemia (AML) have been characterized as diseases that at least in part are caused by a reciprocal translocation between chromosomes 9 and 22, which cytogenetically results in the Philadelphia chromosome (Ph) and molecularly gives rise to the chimeric BCR-ABL1 gene. More than 95% of patients suffering from CML, which is characterized by increased and unregulated proliferation of predominantly myeloid cells in the bone marrow, have been tested positively for this translocation chromosome (Guinn, B. A., et al., Cancer Immunology (2007), CII 56, 943-957). CML occurs most commonly in the middle-aged and elderly and accounts for 15-20% of all cases of adult leukaemia in Western populations. The BCR-ABL1 transcript, encoding a fusion oncoprotein, is present in approximately 25% of patients with B-cell acute lymphoblastic leukaemia (B-ALL).
CML has been found to be caused by the presence of the Ph chromosome in hematopoietic stem cells. Expression of BCR-ABL in hematopoietic cells induces resistance to apoptosis, growth factor independence, and leukomogenesis. While the parent tyrosine kinase c-Abl shuttles between locations at the plasma membrane, actin cytoskeleton, the cytosol and the nucleus, the fusion protein is found only in the cytoplasm and is constitutively active. The tyrosine kinase activity of the fusion protein activates a complex signaling network. It inter alia leads to phosphorylation of Bad as well as constitutive activation of Stat5, thereby enhancing cell survival.
Clinically, the disease can be subdivides into three distinct phases: chronic, accelerated, and blast. Most patients are present in the chronic phase, a stage that is typically indolent in nature. Mature granulocytes are found, but patients typically have an increase in the number of myeloid progenitor cells found in the blood. Left untreated, the disease progresses to the accelerated phase, followed by blast crisis, which is inevitably fatal. During blast phase, hematopoietic differentiation is blocked and blast cells accumulate in the bone marrow and peripheral blood.
Imatinib, a 2-phenylaminopyrimidine derivative, binds to the activation loop of ABL kinase outside of a highly conserved ATP binding site, which traps the kinase in an inactive conformation. Although highly effective, imatinib does not eradicate the disease. Even in patients who demonstrate good response after treatment with a BCR-ABL inhibitor, minimal residual disease is detected at the molecular level using polymerase chain reaction (PCR). Further, a significant minority of patients with newly diagnosed CML in the chronic phase respond poorly to imatinib and are regarded as showing primary resistance. Other patients respond well initially and then lose their response; they may be classified as showing secondary resistance.
In addition, any response observed in patients in the more advanced stages of CML, i.e. accelerated and blastic phases, have been found to typically be short-lived. Further, patients treated with imatinib may eventually develop resistance, particularly those treated in the accelerated or blastic phases. Finally, imatinib treatment has been linked to the potential development of cardiotoxicity in patients with CML.
Currently, a number of further compounds with activity against the BCR-ABL protein kinase are being tested, some of which inhibit the kinase activity of BCR-ABL through mechanisms of action other than interference with the ATP binding site of the kinase. The second-generation BCR-ABL inhibitors nilotinib, a phenylaminopyrimidine derivative, and dasatinib have shown significant activity after imatinib failure, however, particularly in case of dasatinib, associated with untoward off-target toxicities, probably due to their inhibitory activity against a broader range of protein kinases than imatinib. There thus remains a need for alternative treatments of diseases associated with the chimeric BCR-ABL protein.